title: B7-h4 expression in human melanoma: its association with patients' survival and antitumor immune response.
abstract: OBJECTIVE
  Cancers have developed a number of strategies to escape immune responses including the differential expression of costimulatory molecules of the B7 family. B7-H3 and B7-H4 have recently been described in different tumor entities but the relevance for melanoma has not yet been studied so far.
  
  
  METHODS
  Using immunohistochemistry, B7-H3 and B7-H4 expression was studied on 29 melanoma lesions. Survival curves and log-rank tests were used to test the association of protein expression with survival. Cell lines were evaluated for B7-H3 and B7-H4 expression by PCR and flow cytometry. Functional T-cell-tumor coculture assays were carried out with in vitro generated tumor transfectants.
  
  
  RESULTS
  B7-H3 and B7-H4 expression was detected in primary tumor lesions (29 of 29 and 28 of 29) and in metastases (28 of 29 and 26 of 29). The numbers of CD68(+) macrophages were significantly lower in patients with low B7-H4 expression, whereas CD8(+) T-cell infiltrates were independent of expression levels. Furthermore, a survival benefit for patients with B7-H4 low expressing melanoma was found, whereas B7-H3 was not associated with any clinical parameter. All 23 melanoma cell lines analyzed expressed B7-H3 and B7-H4 mRNA and protein, but B7-H4 was restricted to intracellular compartments. On silencing of B7-H3 by specific shRNA tumor-associated antigen-specific T cell responses were unaltered. Overexpression of B7-H4 on melanoma cells did not alter the cytotoxicity of different CD8(+) effector cells, but drastically inhibited cytokine production.
  
  
  CONCLUSIONS
  Our study provides for the first time evidence of B7-H4 expression on melanoma cells as a mechanism controlling tumor immunity which is associated with patients' survival.
authors.affiliation: Martin Luther University Halle-Wittenberg, Institute of Medical Immunology, Halle, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Quandt
authors.forename: Eckhard
authors.initials: E
authors.lastname: Fiedler
authors.forename: Diana
authors.initials: D
authors.lastname: Boettcher
authors.forename: Wolfgang Ch
authors.initials: WCh
authors.lastname: Marsch
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018122:B7-1 Antigen / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000401:mortality*; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000401:mortality*; D016019:Survival Analysis; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1
chemical_list: D018122:B7-1 Antigen; D014408:Biomarkers, Tumor; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human